1. Field of the Invention
This invention relates to a new FK-506 type immunosuppressant agent, a C-31 desmethyl, C-19/C-22 cyclic hemiketal analog of FR-900520 (FK-520), Compound I, a novel fermentation process for its production, utilizing the novel microorganism Streptomyces lavendulae ATCC No. 55209. The process involves culturing the microorganism in the presence of FR-900520 under conditions which induce C-31 demethylation and C-19/C-22 cyclic hemiketal formation of FR-900520. Also disclosed is the C-31 methylated derivative of Compound I, designated as Compound II, produced by enzymatic methylation of Compound I using DIMT, a methyl transferase enzyme. Also disclosed is a method of its use in a human host for treatment of autoimmune diseases, infectious diseases and/or prevention of organ transplant rejections.
2. Brief Description of Disclosures in the Art
In 1983, the US FDA approved cyclosporin, and extremely effective anti-rejection drug that revolutionized the field of organ transplant surgery. The drug acts by inhibiting the body's immune system from mobilizing its vast arsenal of natural protecting agents to reject the transplant's foreign protein.
As effective as the drug is in fighting transplantation rejection, it suffers drawbacks in causing kidney failure, liver damage and ulcers which in many cases can be very severe.
EPO Publication No. 0184162 to Fujisawa, hereby incorporated by reference, describes a new macrolide immunosuppressant FK-506 which is reputed to be 100 times more effective than cyclosporin. The macrolide is produced by fermentation of a particular strain of Streptomyces tsukubaensis. Also described is the closely related macrolide immunosuppressant FR-900520, produced by S. hygroscopicus subsp. yakushimaensis. The terms "FK-520" and "immunomycin" are also used by Merck & Co. Inc. as synonyms for FR-900520.
U.S. Pat. No. 3,244,592 to T. Arai describes the culturing of Streptomyces hygroscopicus var. ascomyceticus to produce the antifungal "ascomycin", which has been shown to be the same compound as FR-900520.
There is, however, no description in the literature of the production of any FK-506 type immunosuppressive agents, which substantially lack the side effects or similar side effects to cyclosporin.
In this regard, new FK-506 type immunosuppressants are continuously being searched for.